The present invention generally relates to the field of oncology and a method of injecting radionuclides for tumor therapy, and more particularly to the use of a class of lipid soluble radioactive metal chelate compounds for treatment of malignant, benign, or inoperable tumors.
Intratumoral injection of certain radionuclides for therapy is drawing increasing attention. (Shyh-Jen Wang, Wan-Yu Lin, Min-Nan Chen, Ching-Shiang Chi, Jung-Ta Chen, William-L Ho, Bor-Tsung Hsieh, Lie-Hang Shen, Zei-Tsan Tsai, Gann Ting, Saed Mirzadeh and Furn F. Knapp, Jr. Intratumoral Injection of Rhenium-188 Microspheres into an Animal Model of Hepatoma. J Nucl Med 39:1752-1757, 1998). Investigators have begun to use intratumoral therapy, especially where tumors are inoperable or where incision of tumors is associated with high risks to the patient. Radionuclide therapy is particularly useful for treating a variety of tumors, including inoperable tumors; prostate tumors, for example, which are confined but are associated with high risk following surgical intervention; and brain tumors such as glioma.
The use of radioactive metal chelates, in general, and Indium-111 lipid soluble complexes, in particular, is based upon work with such agents in the diagnostic imaging field, especially for labelling cellular blood elements. For example, two of the lipid soluble chelates of Indium-111 have been prepared previously. These compunds are Indium-111-oxine (8-hydroxyquinoline; see M L Thakur, R E Coleman, and M J Welch, Indium-111-labeled leukocytes for the localization of abscesses: preparation, analysis, tissue distribution, and comparison with gallium-67 citrate in dogs. J Lab Clin Med 89: 217-228, 1977) and Indium-111-Merc (Mercapto pyridine-N-oxide; see Thakur M L, McKenney S L, Park C H. Evaluation of Indium-111-2-mercaptopyridine-N-oxide (Merc) for labeling leukocytes in plasma: A kit preparation. J Nucl Med 26: 518-523, 1982). The lipid soluble nature of these compounds is an important characteristic. When these lipid soluble compounds are placed in the presence of any cell, they are capable of passively diffusing through the cell membrane. As a result, Indium-111-oxine has been used to lable blood cells, bacteria, and tumor cells. (Thakur M L, Lavender J P, Arnot R N, Silvester D J, and Segal A W. Indium-111-Labeled Autologous Leukocytes in Man. J Nucl Med 18: 1014-1021, 1977; Thakur M L. Live bacteria labeled with 111In. Eur J Nucl Med 13:266, 1987; Rosenberg S A, Lotze M T, Muul L M, Chang A E, Avis F P, Leitman S, Linehan W M, Robertson C N, Lee R E, Rubin J T, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. NEJM 316: 889-897, 1987).
A comparison between Indium-111-oxine and Indium-111-Merc has shown that Indium-111-Merc has a higher thermodynamic stability and is smaller in size than Indium-111-oxine. These differences result in the more efficient labeling of cells under physiologic conditions by Indium-111-Merc. Whereas Indium-111-Merc can label cells in the presence of plasma, Indium-111-oxine cannot efficiently label cells unless such cells are suspended in balanced salt solutions, such as isotonic saline. In either case, whether in the oxine or Merc form, once Indium-111 has entered the cells, it firmly binds to cell cytoplasmic components and does not come out of the cells. (See U.S. Pat. No. 4,443,426 by Thakur, Madhukar L.; Thakur, M L and McKenney, S M, Indium 111-mercaptopyridine-N-oxide-labeled human leukocytes and platelets: Mechanism of labeling and intracellular location of 111In and mercaptopyridine N-oxide, J Lab Clin Med, 107:141-147, 1986; Thakur, M L, Segal, A W, Louis, L, Welch, M J, Hopkins J, and Peters, T J, Indium-111-Labeled Cellular Blood Components: Mechanism of Labeling and Intracellular Location in Human Neutrophils, J Nucl Med, 18:1020-1024, 1977; Thakur et al., J Lab Clin Med, 89: 217-228, 1977).
Through the Auger electrons Indium-111 emits during its decay (txc2xd=67 hrs), each atom of Indium-111 delivers 0.135 rad of radiation dose to a cell 10xcexc in diameter. The path range of Auger electrons is 8 to 12.5xcexc. (Silvester, D J, Consequences of Indium-111 decay in vivo; calculated absorbed radiation dose to cells labelled by Indium-111 oxine, J of Labelled Compounds and Radiopharmaceuticals, 13: 196-197, 1977). Indium-111 also decays by the emission of two xcex3-rays of 173 Kev (89%) and 247 Kev (94%). These two xcex3-rays are useful for scintigraphic imaging.
The present invention takes advantage of the lipid soluble nature of Indium-111 complexes, along with the radioactive properties of these complexes, and utilizes the radioactive metal chelate as a means of treating tumors. The present invention is distinct from receptor-specific agents, such as radiolabeled antibodies or radiolabeled peptides and is distinct from metabolic agents, such as radiodeoxyuridine. By injecting Indium-111-oxine or Indium-111-Merc into a tumor, the Indium-111 atoms enter the tumor cells, bind to tumor cell cytoplasmic components, and deliver high enough radiation dose to the cell DNA such that apoptosis will occur, thereby arresting cell proliferation and/or leading to tumor regression. Chromosomal aberrations in lymphocytes labeled with Indium-111 have been demonstrated. (ten Berge R J M, Natarajhan, A T, Hardeman M R, et al: Labeling with Indium-111 has detrimental effects on human lymphocytes: concise communication. J Nucl Med 24:615-620, 1983).
While Indium-111 is one example of an appropriate radioactive metal chelate for tumor therapy, other lipid soluble radioactive chelate could be used, so long as such compounds bind tightly to cell cytoplasmic components. Such alternative lipid soluble compounds include Indium-111-tropolone (2-hydroxy-2,4,6-cylcoheptatrienone), Rhenium-186 or Rhenium-188 chelated with sesta-MIBI (methoxy isobutyl isonitrile), HMPAO, or tetrofosnine. (Holman B L, Jones A G, Lister-James J, et al. A new Tc-99m-labeled myocardial imaging agent, hexakis (tbutylisonitrile) technetium (I) [Tc-99m TBI]: initial experience in the human. J Nucl Med 25:1350-1355, 1984; Volkert W A, Hoffman T J, Seger R M, Troutner D E, Holmes R A. 99mTc-propylene amine oxime (99mTc-PnAO); a potential brain radiopharmaceutical. Eur J Nucl Med 9:511-516 1984; Kelly J D, Forster A M, Higley B, et al. Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med 34:222-227, 1993).
In addition to inoperable tumors, certain types of prostate tumors, and brain tumors, such radioactive metal chelates could be directed against a variety of other tumors, including hepatoma, melanoma, breast cancer, pancreatic cancer, lung cancer, sarcomas, and carcinoids. Known metastatic tumors can also be treated similarly. The success of the agent used depends upon its homogeneous distribution into the tumor mass. Such a homogeneous distribution is dependent upon the skill and judgment of a physician injecting the agent. As is customary with many therapeutic agents, repeated injections of the agent may be necessary, depending upon the individual patient and the size, location, and type of tumor targeted for therapy. Typically 1mCi of Indium-111 injected into a 1 cc tumor (1.3xc3x971013 atom and 109 cells) will deliver 17.5 Gy/cell where distribution of the compound is uniform.
In the present invention, it is important to note that the emission of gamma rays by such radioactive metal chelates may lead to delivery of some radiation to normal organs and tissue within vicinity of the targeted tumor. Such expected radiation dose the normal organs and tissue will have to be determined prior to administration of the therapeutic dose.
Nonetheless, the results of work with the present invention have shown that the radioactivity remains in the tumor and does not spread in the body (22 days observation time); tumor growth is arrested; and treated mammals did not lose body weight when compared to untreated tumor-bearing mammals of the same species.
DEFINITIONS
To arrest tumor cell proliferation means to inhibit cell proliferation, to slow the rate of cell proliferation, to arrest cell proliferation, or to kill tumor cells.
The present invention is a method of injecting a class of lipid soluble radioactive metal chelate compounds for intratumoral treatment of malignant, benign, metastatic, or inoperable tumors. The present invention also involves a multisquirter device used to inject the lipid soluble radioactive metal chelate compounds for intratumoral treatment, where the device is designed such that a compound injected with said needle is distributed radially in a uniform volume.
Accordingly, it is an object of the present invention to provide a method of treating a tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to a tumor to arrest tumor cell proliferation.
It is another object of the present invention to provide a method of treating a tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate intratumorally to arrest tumor cell proliferation, wherein said radioactive metal chelate is one of the group of Indium-111-oxine, Indium-111-Merc, Indium-111-tropolone, Rhenium-186 HMPAO, Rhenium-188 HMPAO, Rhenium-186 sestaMIBI, or Rhenium-188 sestaMIBI.
It is yet another object of the present invention to provide a method of treating a tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate intratumorally to arrest tumor cell proliferation, wherein said lipid soluble radioactive metal chelate consists of a radionuclide from one of the group of Indium-114m, Sn-113, Dy-159, Co-56, Fe-59 Cu-67, Y-90, Ru-97, Ru-103, Pd-103, Cd-115, Sn-117, Te-118, Te-123, Ba-131, Ba-140, Gd-149, Gd-151, Tb-160, Re-186, Re-188, Au-198, or Au-199.
It is another object of the present invention to provide a method of treating a tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate intratumorally to arrest tumor cell proliferation, wherein said lipid soluble radioactive metal chelate consists of a chelating agent having a functional group to chelate metal ions with valency states 1 to 7 and said functional group consists of one of the group of OH, NH, NH2, NO2, N3, SH, CO, PO4, CN, NCS, P2O7, SCN, S2O3, with donor atoms of C, N, O, P, or S.
It is a further object of the present invention to provide a method of treating a prostate tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to a prostate tumor to arrest prostate tumor cell proliferation.
It is a further object of the present invention to provide a method of treating a prostate tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said prostate tumor to arrest cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating a prostate tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said prostate tumor to arrest cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.
It is another object of the present invention to provide a method of treating an inoperable tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said inoperable tumor to arrest inoperable tumor cell proliferation.
It is a further object of the present invention to provide a method of treating an inoperable tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said inoperable tumor to arrest inoperable tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating an inoperable tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said inoperable tumor to arrest inoperable tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.
It is another object of the present invention to provide a method of treating a brain tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said brain tumor to arrest tumor brain tumor cell proliferation.
It is a further object of the present invention to provide a method of treating a brain tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said brain tumor to arrest brain tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating a brain tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said brain tumor to arrest brain tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.
It is another object of the present invention to provide a method of treating a hepatoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said hepatoma to arrest hepatoma cell proliferation.
It is a further object of the present invention to provide a method of treating a hepatoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said hepatoma to arrest hepatoma cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating a hepatoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said hepatoma to arrest hepatoma cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.
It is another object of the present invention to provide a method of treating a melanoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said melanoma to arrest melanoma cell proliferation.
It is a further object of the present invention to provide a method of treating a melanoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said melanoma to arrest melanoma cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating a melanoma in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said melanoma to arrest melanoma cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.
It is another object of the present invention to provide a method of treating a metastatic tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said metastatic tumor to arrest metastatic tumor cell proliferation.
It is a further object of the present invention to provide a method of treating a metastatic tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said metastatic tumor to arrest metastatic tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-oxine.
It is another object of the present invention to provide a method of treating a metastatic tumor in a mammal, comprising administering a therapeutically effective amount of a lipid soluble radioactive metal chelate to said metastatic tumor to arrest metastatic tumor cell proliferation, where said lipid soluble radioactive metal chelate is Indium-111-Merc.